Phenotype delineation of ZNF462 related syndrome

Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.     

Behavioral effects of stimulating positive reward sites in the central tegmentum of rhesus monkeys.

Rhesus monkeys with electrodes chronically implanted in reward sites in central tegmentum were given telemetered brain stimulation while they were free ranging alone or with cagemates. Stimulation seemed to induce a relaxed positive affect as measured by increased huddling, increased lipsmacking, reduced muscle tone, increased solicitation of grooming and increased grooming of other monkeys. Stimulation did not increase dominant/submissive interactions and seemed to have no effect on aggression or fear. These results are very different from those obtained from an anterolateral hypothalamic self-stimulation site and indicate that fibers which provide input from this area to anterolateral hypothalamus are not solely responsible for effects obtained in the anterolateral hypothalamic area.     

Single-tube mixed agglutination test for the detection of staphylococcal protein A.

A simple, rapid mixed agglutination test using sheep erythrocytes (SRBC) sensitized with rabbit hemolysin and intact viable staphylococci is described for the detection of bound staphylococcal protein A. Soluble protein A was heat extracted from 50 clinical isolates as well as the Cowan I and Wood 46 strains of Staphylococcus aureus and titered by a hemagglutination test using sensitized SRBC and dilutions of soluble protein A. Protein A could be detected in all of these supernatants including that of S. aureus Wood 46, a strain generally considered to be protein A negative. These organisms were later retested by the mixed agglutination test and even those staphylococcal isolates expressing very low heat-extractable soluble protein A concentrations (1:2 titers) were positive, confirming the sensitivity of the test. In a screen of clinical isolates, only 4 of 235 (1.8%) coagulase-positive isolates were negative in the mixed agglutination test. Of 25 coagulase-negative isolates, none yielded a positive reaction.     

Synergistic actions of pemphigus vulgaris IgG,Fas-ligand and tumor necrosis factor-α during induction of basal cell shrinkage and acantholysis

This study tested a recently proposed “Basal Cell Shrinkage” hypothesis of pemphigus acantholysis through a quantitative analysis of individual and cooperative effects of pemphigus vulgaris (PV) IgG, Fas-ligand (Fas-L) and tumor necrosis factor-α (TNFα) on keratinocyte (KC) volume (i.e. cell size) and adhesive properties. Exposure of KC monolayers and MatTek EpiDermFT? tissues cultures to the physiologic concentrations of Fas-L, TNFα or IgGs from two PV patients resulted in various degrees of reversible changes, which were not observed in control cultures either exposed to normal IgG or left intact. Within 12–24 h of exposure, basal cells in experimental cultures lost their ability to form stress fibers, retracted cytoplasmic aprons and formed keratin aggregates, indicating that their cytoskeleton collapsed. The cell volume decreased significantly (p < 0.05) as the polygonal cell shape changed to a round one. The shrunk cells detached from their neighbors and the substrate, resulting in a reciprocal increase of both the areas of acantholysis and the number of detached KCs, respectively. Since in the skin of PV patients, KCs are targeted by autoantibodies concomitantly with being exposed to autocrine and paracrine pro-apoptotic and pro-inflammatory cytokines, we combined PV IgG with Fas-L and/or TNFα in the cell culture experiments. This amplified several fold an ability of PV IgG to cause basal cell shrinkage and detachment. The obtained results demonstrated for the first time that PV IgG works together with Fas-L and TNFα to induce acantholysis via basal cell shrinkage, which provides a novel mechanism explaining successful treatment of PV patients with TNFα inhibitors.     

Anti‐erosive effects of fluoride and phytosphingosine: an in vitro study

A selection of commercially available products containing stannous fluoride (SnF₂)/sodium fluoride (NaF), SnF₂/amorphous calcium phosphate (ACP), SnF₂/NaF/ACP, tin (Sn)/fluorine (F)/chitosan were compared with phytosphingosine (PHS) with respect to their anti‐erosive properties in vitro. One‐hundred and twenty bovine enamel specimens were immersed in the respective product slurries for 2 min, twice daily. The formulations were diluted with either remineralization solution or artificial saliva. After each treatment, an erosive challenge was performed for 10 min, twice daily, using citric acid, pH 3.4. The specimens were stored in remineralization solution or artificial saliva until the next treatment‐erosion challenge. After 10 d, tissue loss was determined using profilometry. Enamel softening was determined through surface microhardness measurements. Tissue‐loss values (measured in μm and expressed as mean ± SD) for PHS, SnF₂/NaF, SnF₂/ACP, SnF₂/ACP/NaF, and Sn/F/chitosan treatment groups and for the negative‐control group, were, respectively, 35.6 ± 2.8, 15.8 ± 1.8, 22.1 ± 2.0, 22.9 ± 1.8, 16.2 ± 1.2, and 51.2 ± 4.4 in the presence of remineralization solution and 31.7 ± 3.3, 15.6 ± 2.9, 16.5 ± 2.7, 16.8 ± 2.1, 13.1 ± 3.0, and 50.7 ± 2.8 in the presence of artificial saliva. There were no significant differences in surface microhardness measurements between the treatment groups. In conclusion, PHS resulted in a significant reduction of tissue loss compared with the negative control, but in comparison, the toothpastes containing Sn²⁺ and F^? ions were significantly more effective compared with PHS.     

Role of Coronary Flow Velocity in Predicting Adverse Outcome in Clinical Practice

There is a lack of information on the prognostic value of local high velocity in coronary arteries during echocardiography. The aim of the study described here was to define the prognostic value of local velocity >70?cm/s in the left main, anterior or circumflex artery during echocardiography. There were 412 patients in the prospective study. Death, non-fatal myocardial infarction, acute pulmonary edema, acute coronary syndrome and revascularization were defined as major adverse cardiac events (MACEs). Over 10.5?mo, there were 207 patients with MACEs. Seventeen patients died, 10 had non-fatal acute cardiac events and 184 underwent revascularization. Deaths occurred in patients with high local velocity (6.4% vs. 0%, p?<0.009). Acute cardiac events occurred in 10% versus 0% (p?<0.003). MACEs were observed in 62% versus 0% (p?<0.0000001). Only maximal velocity was an independent prognostic predictor of death (odds ratio?=?1.02, 95% confidence interval: 1.01–1.03, p?<0.02) and MACEs (odds ratio?=?1.04, 95% confidence interval: 1.02–1.05, p?<0.0001). The success rate of coronary artery visualization for at least one segment was 91%.